WO1994022448A1 - Utilisation topique ou systemique de buspirone ou de derives de celle-ci pour le traitement de troubles pathologiques associes a des reactions immunitaires - Google Patents

Utilisation topique ou systemique de buspirone ou de derives de celle-ci pour le traitement de troubles pathologiques associes a des reactions immunitaires Download PDF

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Publication number
WO1994022448A1
WO1994022448A1 PCT/US1994/003353 US9403353W WO9422448A1 WO 1994022448 A1 WO1994022448 A1 WO 1994022448A1 US 9403353 W US9403353 W US 9403353W WO 9422448 A1 WO9422448 A1 WO 9422448A1
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Prior art keywords
alkyl
aryl
buspirone
group
heterocycle
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PCT/US1994/003353
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English (en)
Inventor
Richard J. Sharpe
Kenneth A. Arndt
Stephen J. Galli
Peter C. Meltzer
Raj K. Razdan
Howard P. Sard
Original Assignee
Beth Israel Hospital Association
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Publication date
Priority claimed from US08/037,271 external-priority patent/US5484788A/en
Priority claimed from US08/037,225 external-priority patent/US5631017A/en
Application filed by Beth Israel Hospital Association filed Critical Beth Israel Hospital Association
Priority to AT94911001T priority Critical patent/ATE241359T1/de
Priority to DE69432749T priority patent/DE69432749T2/de
Priority to CA002159091A priority patent/CA2159091C/fr
Priority to EP94911001A priority patent/EP0690715B1/fr
Priority to JP6522262A priority patent/JPH09502699A/ja
Priority to DK94911001T priority patent/DK0690715T3/da
Priority to AU63692/94A priority patent/AU692764B2/en
Publication of WO1994022448A1 publication Critical patent/WO1994022448A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the immune system specifically recognizes and selectively eliminates foreign invaders, or other antigenic agents, by a process known as the immune response.
  • the immune response has three major characteristics: it responds adaptively to foreign invaders, it exhibits strong specificity, and it displays a long-term memory of earlier contacts with specific foreign pathogens or antigens.
  • the immune response involves the production of
  • T lymphocytes are highly specific for the antigen or hapten.
  • the immune response When directed against an infectious organism, the immune response can provide great benefit to the host.
  • an important component of current public health practices is the use of vaccines to elicit immune responses against infectious organisms that cause severe illness and death.
  • agents that are relatively innocuous such as pollen, animal dander, and certain plant resins
  • the cells, antibodies, and mediators which represent the effector components of the immune response can cause damage to the host's tissues that is out of proportion to any threat to health posed by the antigenic agent that first elicited the response.
  • Topical disorders that involve the immune system can result in result in one or more of the
  • Cutaneous contact hypersensitivity responses are complex expressions of cellular immunity
  • T cells are required for the expression and immunological specificity of the response, many other cell types also have roles in the reaction, including
  • Langerhans' cells Langerhans' cells, keratinocytes, and vascular endothelial cells. Antigen presentation is thought to be effected primarily by Langerhans' cells, whereas much of the local expression of the response is thought to be regulated by cytokines derived from both T cells and accessory cells.
  • serotonin (5-hydroxytryptamine, 5-HT)
  • serotonin has been shown to have a wide range of actions on T cells and other effector cells in vitro or in vivo , and pharmacological agents that deplete or
  • antagonize serotonin can diminish expression of cell-mediated immunity.
  • Early studies raised the possibility that such agents might reduce cell- mediated immunity by antagonizing or depleting mast cell-associated serotonin.
  • more recent findings indicate that at least one of these drugs, reserpine, can inhibit contact hypersensitivity independently of mast cells, probably through direct effects on T cells.
  • cutaneous contact hypersensitivity responses can occur on exposure to certain plant resins, such as those of poison ivy, and other commonly encountered agents in the environment. In individuals sensitized to such commonly encountered agents, a severe contact reaction can result upon exposure, with significant associated morbidity. Severe or repeated contact hypersensitivity reactions can be followed by significant chronic changes, such as scarring of affected tissues, itchiness, swelling, scaling and oozing of tissue fluid through the skin surface. This pathology may predispose the patient to bacterial superinfection. In the eye, chronic immune responses can lead to diminished vision or actual blindness. In the lung, chronic immune responses, such as chronic allergic asthma, can result in serious chronic lung disease.
  • hypersensitivity including systemic disorders, include but are not limited to host rejection of foreign organ or tissue transplants; graft-vs-host disease in which donor immunological cells present in the graft attack host tissues in the recipient of the graft; diseases with proven or possible autoimmune components, such as rheumatoid arthritis and juvenile rheumatoid arthritis, aphthous ulcer, lichen planus, psoriatic arthritis, psoriasis, excema, conjunctivitis, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, ulceris, alopecia areata, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, multiple sclerosis, allergic encephalomyelitis, systemic lup
  • immunosuppressants including steroid hormones, antiproliferatives such as methotrexate and azathioprine, cyclosporine, alkylating agents such as cyclophosamide and busulfan, psoralen plus ultraviolet A (PUVA), and antibiotics.
  • steroid hormones such as methotrexate and azathioprine
  • cyclosporine such as cyclosporine
  • alkylating agents such as cyclophosamide and busulfan
  • PUVA psoralen plus ultraviolet A
  • Corticosteroids when administered systemically, can be effective but can be associated with
  • Topically applied corticosteroids have some efficacy in treating these conditions, but are only partially effective in many instances and have their own significant side effects, including atrophy of tissue, formation of telangiectasia, blanching, and a myriad of systemic effects if significantly absorbed. As a result, there still remains a strong need to provide new
  • immunosuppressive agents that can minimize or prevent pathological immune responses.
  • inflammatory response is a pathologic condition that can occur in response to immunologically non-specific injury, either from physical (such as trauma), chemical, or biological agents.
  • An inflammatory response is characterized by increased blood flow and redness in the inflamed area, increased capillary permeability and edema, and recruitment of immunologically non-specific white blood cells, especially neutrophils, that remove injurious material and promote repair.
  • inflammatory responses do not respond adaptively to the inciting stimulus, do not show specificity and do not exhibit long term memory.
  • Cellular products of lymphocytes may contribute to or induce an inflammatory response.
  • a compound can function as an anti-inflammatory agent without having immunosuppressive properties.
  • Phenylbutazone, indomethacin, aspirin, ibuprofen, and acetaminophen are examples of anti-inflammatory compounds which have no significant
  • immunologically mediated responses such as contact hypersensitivity.
  • PCT International Publication No. WO 91/02527 discloses a method and composition to treat cutaneous, mucosal, or ocular hypersensitivity that includes administering an effective amount of reserpine, spiperone, or other serotonin
  • invention to present a method for the systemic treatment of pathogenic conditions associated with immune responses.
  • a method for the treatment of a human or other mammal in need of immunosuppression is disclosed in which the mammal is treated topically or
  • buspirone or a buspirone derivative in a pharmaceutically- acceptable diluent or carrier for topical or systemic administration.
  • Buspirone and its active derivatives can be administered as general immunosuppressive agents to treat a variety of disorders.
  • a method is provided for the treatment of a
  • buspirone or a buspirone derivative or its pharmaceutically acceptable salt in a pharmaceutically-acceptable diluent or carrier for topical application.
  • the compounds are useful as topical agents in treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome,
  • keratoconjunctivitis sicca secondary to Sjogren's Syndrome including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, ulceris, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.
  • the compounds may also be useful in reducing the infiltration of skin by malignant leukocytes in diseases such as mycosis fungoides. These compounds are also effective in treating an aqueous-deficient dry eye state (such as immune mediated keratoconjunctivitis) in a patient suffering therefrom, by administering the compound topically to the eye.
  • buspirone or its derivative is administered systemically for the treatment of systemic or topical disorders involving the immune system.
  • the parent buspirone can have a neuroleptic effect when administered systemically (but not typically when administered topically), however, it is a model of an active immunosuppressant.
  • Derivatives of buspirone are considered to be immunosuppressants if they suppress the ear swelling associated with an experimental contact hypersensitivity response by at least 40% at 24 hours after specific antigen challenge.
  • Figure 1 Effect of topically administered buspirone HCl on tissue swelling associated with oxazolone-induced contact hypersensitivity
  • Oxazolone (10 ⁇ l of a 0.5% (w:w) solution) was applied to both ears of all mice and the change in ear thickness was measured at a specified interval thereafter.
  • Buspirone HCl 100 mg/ml (Group B) or vehicle alone (Group A) was applied to the right ear of Balb/c mice 2 hours after challenge.
  • the change in ear thickness (post-challenge value minus baseline pre-challenge value) was measured 24 hours after oxazolone challenge.
  • the data are presented as the mean ⁇ SEM (standard error of the mean).
  • Figure 3 Comparative effects of 50 mg/kg subcutaneous administration of mianserin HCl (Group A) , trazadone HCl (Group B), haloperidol (Group C), buspirone HCl (Group D), and vehicle (Group E) on the tissue swelling associated with oxazolone- induced cutaneous contact hypersensitivity
  • Buspirone HCl, the other agents, or vehicle alone were administered to BALB/c mice 1 hour after right ears only were challenge for contact hypersensitivity.
  • the change in ear thickness (post-challenged value minus baseline pre-challenge value) was measured 24 hours after oxazolone challenge.
  • the data are presented as the mean ⁇ SEM.
  • Figure 4 Comparative effects of subcutaneous administration of 50 mg/kg mianserin HCl (Group A), trazadone HCl (Group B), haloperidol (Group C), buspirone HCl (Group D), and systemic vehicle
  • Oxazolone was applied to both ears of all mice at different times either pre- or post- buspirone HCl treatment and the change in ear thickness was measured at a specified interval thereafter. a. Two hours before oxazolone
  • buspirone HCl in Vehicle-N was applied to both surfaces of the right ears of Group B mice, whereas vehicle alone (0% buspirone HCl) was applied to both surfaces of the ears of control vehicle only
  • mice (Group A vehicle-N) mice.
  • the change in ear thickness was determined 24 hours after treatment with buspirone HCl, i.e. at 48 hours after
  • Buspirone HCl (Groups A and B) or vehicle alone (Group C) was administered to Balb/c mice 1 hour after challenge. Change in ear thickness (postchallenge - baseline pre-challenge value) was measured 24 hours after oxazolone challenge. The data are presented as ⁇ SEM. Systemic treatment with buspirone HCl (at 500 or 50 mg/kg)
  • FIG. 9 The effect of topical treatment with buspirone HCl on suppression of the sensitization phase of oxazolone challenge.
  • Buspirone HCl at 100 mg/ml (Group A) or vehicle-N (Group B) was applied to abdomen of mice 3 days prior to sensitization of Balb/c mice with 4% oxazolone. This treatment was repeated 3 days after sensitization. The right ears of all mice were then challenged with 0.5% oxazolone. The change in the ear thickness was measured 24 hours after oxazolone challenge. The data are presented as the mean ⁇ SEM. The
  • FIG. 10 Effect of topical treatment with buspirone HCl (100 mg/ml) on leukocyte infiltration associated with suppression of sensitization phase of oxazolone challenge. These data are from the same mice whose ear thickness measurements are presented in Fig. 9. Biopsies were performed 24 hours after oxazolone challenge.
  • FIG 11 Effect of systemic buspirone HCl treatment (50 mg/kg, administered subcutaneously), indomethacin, or placebo pellets (0.05 mg/pellet, implanted subcutaneously) on oxazolone induced contact hypersensitivity.
  • Four groups of mice were sensitized to oxazolone by treatment with 4% oxazolone. Three days later two groups were implanted with 0.05 mg indomethacin (Group A) and placebo pellets (Group B). Three days later, right ears of mice in all four groups were challenged with 0.5% oxazolone.
  • One hour post challenge, remaining two groups were treated with buspirone HCl at 50 mg/kg (Group C) or vehicle (Group D). Ear swelling was measured 24 hours after oxazolone challenge.
  • FIG. 12 Effect of systemic buspirone HCl treatment (Group C), indomethacin or placebo treatment (Groups A and B, respectively) on leukocyte infiltration associated with oxazolone induced cutaneous hypersensitivity reaction.
  • These data are from the same mice whose ear thickness measurements are presented in Fig. 11. Biopsies were performed 24 hours after oxazolone challenge.
  • alkyl as used herein, unless otherwise specified, refers to a saturated straight
  • branched, or cyclic hydrocarbon of C 1 to C 20 including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3- dimethylbutyl.
  • aryl refers to phenyl or
  • substituted phenyl wherein the substituent is independently halo, alkyl, or oxy( alkyl) (for example, methyoxy, ethoxy, etc.), and wherein the aryl can have up to three substituents.
  • heterocycle refers to a cyclic moiety that has O, S, or N in the aromatic ring, including but not limited to, pyrryl, furyl, pyridyl, thiophene, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbozolyl, and isoxazolyl and the like, optionally substituted with halo (Cl, Br, I, or F), alkyl, oxyalkyl, aryl or oxyaryl.
  • halo Cl, Br, I, or F
  • aralkyl refers to an aryl group with an alkyl substituent.
  • alkaryl refers to an alkyl group that has an aryl substituent.
  • alkene refers to an alkene group of C 2 to C 10 , and specifically includes vinyl, and allyl.
  • the parent buspirone is 8-[4-[4-(2-pyrimidinyl)- 1-piperaziny]butyl]-8-azaspiro-[4.5]decane-7,9- dione, which has the structure illustrated below.
  • buspirone derivative refers to a compound that exhibits an
  • immunosuppressive effect for example, as measured using the assay set out in Example 1, i.e., it suppresses the ear swelling associated with an experimental contact hypersensitivity response by at least 40% at 24 hours after specific antigen challenge, or as evaluated in vivo in humans by the agent's ability to inhibit contact hypersensitivity responses to patch test allergens in patients hypersensitive to a given allergen, using procedures generally accepted by those of skill in the art, and wherein the derivative has the formula:
  • R 1 H; halo (chloro, bromo, fluoro, or iodo);
  • alkyl specifically including CH 3 -, cyclohexyl, (CH 3 ) 2 CH-, CH 3 (CH 2 ) 3 -,
  • R 2 H, C 6 H 5 CH(CH 2 CH 3 )CH 2 -, C 6 H 5 CH(CH 3 ) (CH 2 ) 2 - ,
  • n 1 to 6;
  • X is independently F, Cl, Br, I, OCH 3 , SO 3 -,
  • Ar 1 independently, aryl, (2, 3, or 4-X-C 6 H 4 -) ,
  • toluenesulfonate methylsulfonate, sulfonate, sulfate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate,
  • propionate maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • buspirone or its derivatives are disclosed in, or can be easily adapted by one of ordinary skill in organic synthesis from procedures disclosed in Wu, et al., J. Med. Chem. 15, 477 (1972), Ger. Patent No.
  • buspirone has significant immunosuppressive
  • buspirone derivatives to act as an immunosuppressant can be conveniently determined by synthesizing the compound and testing it in the biological assay described in Example 1.
  • the active compounds described herein exhibit an immunosuppressive effect when provided topically or systemically.
  • the derivative is considered an immunosuppressant if it suppresses the ear swelling associated with an experimental contact
  • hypersensitivity response by at least 40% at 24 hours after specific antigen challenge.
  • the agent can be evaluated in vivo in humans by assessing the agent's ability to inhibit contact hypersensitivity responses to patch test allergens in patients hypersensitive to a given allergen, using procedures generally accepted by those of skill in the art, or by evaluation in an animal model, for example, of allograft
  • buspirone derivatives of buspirone which are particularly useful are those that have an immunosuppressive effect but which do not exhibit a significant neuroleptic effect, Buspirone derivatives without significant
  • neuroleptic effect can be identified by their ability to bind to serotonin or dopamine receptors, or by assessing their lack of ability to act as a tranquilizer or neuroleptic in mammals, for
  • buspirone and buspirone derivatives are not effective in suppressing contact hypersensitivity.
  • the mechanism of action of buspirone and buspirone derivatives in suppressing the immune response is independent of their serotonin or dopamine receptor blocking properties. Therefore, buspirone derivatives with immunosuppressive effects yet without neuroleptic effects can be provided by the method of selection disclosed generally herein.
  • immunosuppressive compounds with a buspirone nucleus that have a neuroleptic effect can be complexed or modified to eliminate that effect, by one or more of the following processes.
  • Compounds with a buspirone nucleus that exhibit an immunosuppressive effect yet also exhibit a neuroleptic effect can be modified to minimize the neuroleptic effect by decreasing the lipophilicity (equivalent to increasing the hydrophilicity) of the molecule. This can be done by adding one or more charged side chain (s) onto the molecule or by altering the existing side chain to make it more polar. The hydrophilicity of buspirone derivatives will in general increase when charged substituents are added.
  • Another technique for reducing the central nervous system (CNS) effects of compounds that contain a buspirone nucleus is to increase the size of the molecule via a covalent linkage to a large moiety (e.g., albumin or polyethylene glycol), using standard techniques of organic synthesis or by choosing a buspirone derivative with large substituents.
  • a large moiety e.g., albumin or polyethylene glycol
  • a third method for reducing the central nervous system (CNS) effects of a compound that contains a buspirone nucleus includes forming a non-covalent complex of the compound with a cyclic molecule such as a cycloamylose (e.g., a cyclodextrin such as ⁇ -cyclodextrin), which has a spatial arrangement of hydroxyl groups whereby the outer surface of the ring formed by the cycloamylose is hydrophilic and the inner surface is lipophilic.
  • a cyclic molecule such as a cycloamylose (e.g., a cyclodextrin such as ⁇ -cyclodextrin)
  • a cycloamylose e.g., a cyclodextrin such as ⁇ -cyclodextrin
  • guest molecules molecules (or parts thereof), termed “guest molecules”, which are less polar than water and which are of suitable dimensions, to be incorporated into the lipophilic inner cavity, such that the cycloamylose/guest molecule complex presents to the blood-brain barrier as a relatively large and polar compound which is unable to penetrate the barrier.
  • Such complexes may be prepared by any method known to the art, including those described in U.S. Patent No. 4,555,504, which discloses ⁇ -cyclodextrin complexed with digoxin.
  • the central nervous system side effects of a buspirone derivative can be estimated using molecular modeling and/or pharmacophore analysis.
  • the dopamine and serotonin receptors are well characterized and strategies for estimating binding of drugs to these receptors are well established.
  • Buspirone or its above-defined derivative can be administered in the form of a pharmaceutically acceptable quaternary salt.
  • Quaternary salts are typically less lipophilic than the corresponding unquaternized compound, and therefore have a decreased effect on the central nervous system.
  • Nonlimiting examples of quaternary salts that can be used include salts prepared from methyl
  • toluenesulfonate methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, succinate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and
  • methyl ammonium tosylate salt of buspirone has been found to be toxic to mice at elevated dosage levels (above 10 mg/kg). Therefore, this quaternary salt of buspirone or its derivatives should be administered as the lowest dosage that achieves a desired effect.
  • Buspirone or its derivative can be included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects for any of the above described disorders.
  • the concentration of active compound in the drug composition will depend on absorption,
  • dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • Buspirone or its derivative can be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antibiotics,
  • antifungals anti-inflammatories, antivirals, or other immunosuppressive agents.
  • Buspirone or its derivatives can be provided in the form of pharmaceutically-acceptable salts.
  • pharmaceutically-acceptable salts or complexes refers to salts or complexes that retain the desired biological activity of the parent compound and exhibit minimal, if any, undesired toxicological effects.
  • salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,
  • naphthalenesulfonic acids naphthalenedisulfonic acids, and polygalacturonic acid
  • base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium,
  • Buspirone or its derivatives can be modified in order to enhance their usefulness as pharmaceutical compositions.
  • various modifications of the active molecule such as alteration of charge, can affect water and lipid solubility and thus alter the potential for percutaneous absorption.
  • vehicle, or carrier can also be modified to enhance cutaneous absorption, enhance the reservoir effect, and minimize potential irritancy or
  • Compounds that are useful are typically those that have a therapeutic index of at least 2, and preferably 5 or 10 or greater, wherein therapeutic index is defined as EC 50 /IC 50 .
  • Mammals, and specifically humans, suffering from pathological cutaneous, ocular, or mucosal immune responses can be treated by topical administration to the patient of an effective amount of buspirone or its derivative or its salt, optionally in combination with a pharmaceutically acceptable carrier or diluent.
  • the active compound is included in the pharmaceutically acceptable topical carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of the buspirone derivative locally in the absence of serious toxic effects.
  • local immunosuppression can be achieved by topically administering lower doses of buspirone derivatives than would be required if the agents were administered systemically.
  • Typical dosages for topical application for all of the above-identified conditions are those ranging from 0.001 to 100% by weight of the active compound.
  • Solutions or suspensions for topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions,
  • thickening agents examples include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • humectants such as sorbitol
  • emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • solutions and ointments are commercially available, especially for ophthalmic applications.
  • Thickening agents, emollients, and stabilizers can be used to prepare topical compositions.
  • thickening agents examples include petrolatum, beeswax, xanthan gum, or polyethylene glycol, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • humectants such as sorbitol
  • emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • Natural or artificial flavorings or sweeteners can be added to enhance the taste of topical preparations applied for local effect to mucosal surfaces.
  • Inert dyes or colors can be added, particularly in the case of preparations designed for application to oral mucosal surfaces.
  • Buspirone or its derivative can be applied in a time release formulation via transdermal patches or by slow release polymers.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a
  • controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
  • Mammals, and specifically humans, suffering from pathogenic immune responses can also be treated by the systemic administration to the patient of an effective amount of the buspirone derivative or its salt optionally in combination with a
  • the buspirone derivative can be administered, for example, subcutaneously, intravenously, intraperitoneally, intramuscularly, parenterally, orally, submucosally, by inhalation, or
  • Typical systemic dosages for all of the above-identified conditions are those ranging from 20 mg/kg to 0.0001 mg/kg per day as a single daily dose or divided daily doses.
  • the effective dosage of the parent compound, buspirone, for systemic immunosuppression is believed to be higher than the effective dosage of buspirone for inducing a neuroleptic effect.
  • the buspirone derivative is administered
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid,
  • Primogel, or corn starch a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other
  • materials which modify the physical form of the dosage unit for example, coatings of sugar, shellac, or other enteric agents.
  • buspirone derivative or its salts can be administered as a component of an elixir
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous, application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • bacteriostatic water physiological saline
  • Cremophor EL TM BASF, Parsippany, NJ
  • PBS phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body on systemic delivery, such as a controlled release formulationo including implants and
  • Biodegradable, biocompatible polymers can be used, such as
  • polyglycolic acid collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions including liposomes targeted to infected cells with monoclonal
  • antibodies to specific antigens can also be used as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an organic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the buspirone derivative is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
  • Buspirone and buspirone derivatives are capable of acting systemically or topically to suppress the immune response in humans and other mammals.
  • the compounds, or therapeutic compositions thereof are useful for the treatment of a myriad of immunological disorders or other pathological conditions associated with an immune response.
  • disorders include cutaneous contact hypersensitivity, host rejection of foreign organ or tissue transplants; graft-vs-host disease in which donor immunological cells present in the graft attack host tissues in the recipient of the graft; diseases with proven or possible autoimmune components, such as rheumatoid arthritis and juvenile rheumatoid arthritis, aphthous ulcer, lichen planus, psoriatic arthritis, psoriasis, excema, conjunctivitis, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, ulceris, alopecia areata, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, multiple sclerosis, allergic encephalomyelitis, systemic lupus ery
  • dermatitis and hypersensitivity to pollen, insect stings and certain foods can also be useful in reducing the infiltration of skin by malignant leukocytes in diseases such as mycosis fungoides.
  • Buspirone and its derivatives can also be used to increase tear production in a patient suffering from deficient tears in the eye due to an
  • KCS immune mediated keratoconjunctivitis
  • corneal and conjunctival lesions ensues from the dry eye state.
  • Buspirone or its active derivatives can be provided as an ophthalmic drop or ophthalmic ointment to humans or other mammals, including dogs and cats, in an effective amount in a suitable vehicle.
  • This topical ophthalmic treatment can also serve to correct corneal and conjunctival disorders exacerbated by tear deficiency and KCS, such as corneal scarring, corneal ulceration, filamentary keratitis,
  • Buspirone and its derivatives can also be used to decrease immune responses which contribute to granulation and neovascularation in the cornea.
  • Buspirone HCl was used for the procedure in Example 1 as a model of an active immunosuppressant.
  • Buspirone derivatives can be measured against this model, and are considered active if they suppress the swelling response by at least 40% 24 hours after specific antigen
  • buspirone significantly suppressed the tissue swelling associated with the elicitation phase of contact hypersensitivity to oxazolone.
  • mice treated topically with buspirone HCl unlike those treated systemically, exhibited no drowsiness or other evidence of central nervous system
  • Buspirone expresses both serotonin and dopamine receptor antagonist activity. However, unlike buspirone, it was discovered that the chemically unrelated serotonin antagonists, trazadone and mianserin, and the dopamine receptor antagonist, haloperidol, were not effective in suppressing contact hypersensitivity. On the basis of this, it appears that the mechanism of action of buspirone on the immune response is independent of its serotonin or dopamine receptor blocking properties, and therefore, buspirone derivatives with
  • Buspirone HCl, mianserin, trazadone, haloperidol and oxazolone were purchased from the Sigma
  • mice hypersensitivity were performed as follows. The abdomens of the mice were shaved with electric clippers, 50 ⁇ l of a 4% (w/w) solution of oxazolone in 4 : 1 (v:v) acetone: olive oil were applied to the shaved abdomen, and 5 ⁇ l of the same solution were applied to each hind footpad. Five to eight days later, the mice were challenged for contact
  • mice were treated subcutaneously with buspirone HCl 500 or 50 mg/kg body weight) in 0.1 mL of carrier (Cremophor EL, BASF, Parsippany, NJ), or with 0.1 mL of carrier alone.
  • carrier Carrier
  • mice were treated in a similar fashion with 50 mg/kg body weight of trazadone, mianserin, haloperidol, or buspirone HCl in 1 mL olive oil or with olive oil alone.
  • Topical Buspirone HCl Treatment For these experiments, both ears of each mouse were
  • mice Two hours before, or twenty-four hours after application of hapten, the right ears of some mice were treated with buspirone HCl in vehicle, applied epicutaneously to both surfaces. The right ears of control mice were similarly treated, but with vehicle alone. In the case of experiments designed to assess topical effects on the sensitization phase, only the right ear is challenged. (See Figures 9 and 10)
  • ear thicknesses were determined with an engineer's micrometer.
  • the increment (delta) in ear thickness (ear swelling) was calculated as the 24- or 48-hour value minus the baseline (pre-challenge) value and expressed in units of 10 -4 inches. Mice were killed by cervical dislocation after the measurement of 24-hour ear thickness was obtained, and the ears were processed for histologic examination.
  • FIGS. 1 and 2 illustrate the effect of topical application of 100 mg/mL of buspirone HCl (Group B) or carrier alone (Group A) on expression of contact
  • buspirone HCl significantly decreased ear swelling ( Figure 1) and aggregation of leukocytes (Figure 2).
  • HCl was extremely effective in diminishing both the tissue swelling and the leukocyte infiltration associated with contact hypersensitivity reactions, these effects were observed in the absence of detectable alterations in the behavior of the mice.
  • mice treated topically with buspirone HCl appeared active and retained apparently normal interest in food and water.
  • Serotonin or Dopamine Receptor Antagonists systemic buspirone was compared to the serotonin receptor antagonists, trazadone or mianserin, and to the dopamine receptor antagonist, haloperidol, for their ability to inhibit cutaneous contact hypersensitivity. At a dose of 50 mg/kg, only buspirone HCl significantly reduced cutaneous contact hypersensitivity ( Figures 3 and 4).
  • buspirone HCl leukocyte infiltration associated with the response in mice treated with 500 or 50 mg/kg buspirone HCl was also diminished compared to responses in mice not treated with the drug ( Figure 8).
  • buspirone HCl also produced other remarkable systemic effects.
  • mice were sensitized to oxazolone as described in Example 1. Three days later, slow release indomethacin pellets (0.05 mg, 3 week release) were implanted subcutaneously under light ether
  • mice completely block prostaglandin synthesis in mice, by Jun, D.D., et al., J. Invest. Dermatol. 90:311 (1988). Three days later, mice were challenged for contact hypersensitivity as in Example 1. When the hypersensitivity response was assessed 24 hours later, indomethacin was shown to have no
  • Buspirone derivatives which lack serotonin receptor binding or dopamine receptor binding activity can be identified as follows.
  • radiolabeled ligand known to bind serotonin and/or dopamine receptors can be bound to an appropriate substrate expressing one or both of these
  • radiolabeled quipazine which is available commercially can be used as the ligand.
  • the buspirone derivative to be tested is then incubated with the radiolabeled quipazine ligand combination. Displacement of radiolabeled ligand is positive evidence that the buspirone derivative being tested can bind serotonin and/or dopamine receptors.
  • the amount of radiolabeled ligand which is displaced is determined by an appropriate standard curve which can also provide information concerning binding affinities.
  • the displaced radiolabeled ligand can be quantitated using a standard scintillation counter.
  • Binding studies using 3 H-quipazine are described in detail by Milburn, CM. and Peroutka, S.J., J. Neurochem. 52:1787-1792 (1989). Briefly, rat cortices are homogenized in 20 volumes of 50 mM Tris HCl buffer pH 7.7 at 25 °C and centrifuged at
  • the pellet is resuspended in fresh buffer and incubated at 37°C for 10 min. After the final centrifugation, the pellet is resuspended in 80 volumes of Krebs-HEPES buffer (25 mM HEPES, 118 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , and
  • Tissue (10 mg of original wet weight) is added to assay tubes containing 0.8 nM [ 3 H] quipazine and displacing drug or buffer in a final volume of 1 mL.
  • Non-specific binding is defined using 1 micromole zacopride.
  • affinities for dopamine and/or serotonin receptors of one/tenth or less than native buspirone are considered to be potentially useful as systemic immunosuppressants if they are at least 50% as active as native buspirone on a weight basis in suppressing immunologically specific responses such as contact hypersensitivity.

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Abstract

On décrit un procédé pour le traitement de patients ou d'animaux mammifères nécessitant un traitement immunosuppresseur, procédé selon lequel on effectue un traitement topique ou systémique avec une quantité efficace de buspirone ou d'un dérivé de la buspirone, dans un diluant ou un excipient acceptable sur le plan pharmaceutique et permettant une administration topique ou par voie générale.
PCT/US1994/003353 1993-03-26 1994-03-28 Utilisation topique ou systemique de buspirone ou de derives de celle-ci pour le traitement de troubles pathologiques associes a des reactions immunitaires WO1994022448A1 (fr)

Priority Applications (7)

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AT94911001T ATE241359T1 (de) 1993-03-26 1994-03-28 Topische und systemische anwendung von buspiron und seinen derivaten zur behandlung von pathologischen zuständen, die mit immunantworten verbunden sind
DE69432749T DE69432749T2 (de) 1993-03-26 1994-03-28 Topische und systemische anwendung von buspiron und seinen derivaten zur behandlung von pathologischen zuständen, die mit immunantworten verbunden sind
CA002159091A CA2159091C (fr) 1993-03-26 1994-03-28 Application topique et systemique de la buspirone ou de derives de celle-ci pour le traitement de conditions pathologiques associees aux reponses immunitaires
EP94911001A EP0690715B1 (fr) 1993-03-26 1994-03-28 Utilisation topique ou systemique de buspirone ou de derives de celle-ci pour le traitement de troubles pathologiques associes a des reactions immunitaires
JP6522262A JPH09502699A (ja) 1993-03-26 1994-03-28 バスピロン又はその誘導体の局部的及び全身投与に依る免疫反応性病体の治療
DK94911001T DK0690715T3 (da) 1993-03-26 1994-03-28 Topisk og systemisk applikation af busphiron eller derivater deraf til behandling af pathologiske tilstande associeret med immunreaktioner
AU63692/94A AU692764B2 (en) 1993-03-26 1994-03-28 Topical and systemic application of buspirone or derivatives thereof for treatment of pathological conditions associated with immune responses

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US08/037,271 US5484788A (en) 1993-03-26 1993-03-26 Buspirone as a systemic immunosuppressant
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US08/037,271 1993-03-26
US08/037,225 US5631017A (en) 1993-03-26 1993-03-26 Topical application of buspirone for treatment of pathological conditions associated with immune responses

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006601A1 (fr) * 1994-08-30 1996-03-07 Allergan Utilisation des ligands de 5-ht comme agents antiprurigineux
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis
WO1997037659A1 (fr) * 1996-04-08 1997-10-16 Sano Corporation Dispositif pour administration transdermique de composes d'azapirone

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CN1114401C (zh) * 1998-07-14 2003-07-16 阿尔康实验室公司 11－(3－二甲氨基亚丙基)－6,11－二氢二苯并[b,e]噁庚英－2－乙酸用于制药的新用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE759371A (fr) * 1969-11-24 1971-05-24 Bristol Myers Co Azaspirodecanediones heterocycliques et procedes pour leur preparation
US3976776A (en) * 1972-12-06 1976-08-24 Mead Johnson & Company Tranquilizer process employing N-(heteroarcyclic)piperazinylalkylazaspiroalkanediones
ATE135216T1 (de) * 1989-08-21 1996-03-15 Beth Israel Hospital Verwendung von spiperone-derivate zur immunosuppression
ATE171067T1 (de) * 1990-03-16 1998-10-15 Beth Israel Hospital Verwendung von spiperon als immunsuppressivum und antiinflammatorisches mittel
SE513429C2 (sv) * 1992-06-03 2000-09-11 Syntello Inc Preparat för aktivering av naturliga mördarceller, vilket preparat innehåller interferon alfa och biogena aminer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006601A1 (fr) * 1994-08-30 1996-03-07 Allergan Utilisation des ligands de 5-ht comme agents antiprurigineux
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis
WO1997037659A1 (fr) * 1996-04-08 1997-10-16 Sano Corporation Dispositif pour administration transdermique de composes d'azapirone

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ES2201074T3 (es) 2004-03-16
EP0690715A1 (fr) 1996-01-10
DE69432749D1 (de) 2003-07-03
DK0690715T3 (da) 2003-09-22
JPH09502699A (ja) 1997-03-18
CA2159091C (fr) 2006-12-19
AU692764B2 (en) 1998-06-18
EP0690715A4 (fr) 1997-09-03
DE69432749T2 (de) 2004-04-08
PT690715E (pt) 2003-10-31
AU6369294A (en) 1994-10-24
ATE241359T1 (de) 2003-06-15
EP0690715B1 (fr) 2003-05-28

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